Preparation of aspirin



United States Patent Office 3,235,583 PREPARATION OF ASPIRIN Robert T. Edmunds, Norwich, N.Y., assignor to The Norwich Pharmacal Company, Norwich, N.Y., a corporation of New York No Drawing. Filed July 22, 1964, Ser. No. 384,544 3 Claims. (Cl. 260--480) This invention relates to an improved method of preparing aspirin (acetyl salicylic acid) and is a continuation-in-part of my earlier filed pending application, Serial No. 126,440, filed July 14, 1961, and now abandoned, which, in turn, was a continuation-in-part of my copending application Serial No. 819,236, filed June 10, 1959, and now abandoned.

For many years the method customarily employed to prepare aspirin of a degree of purity that is acceptable for pharmaceutical purposes, and in a form that lends itself to the ready tableting of the aspirin, involved a multi-step method which is both cumbersome and expensive. In that method, salicylic acid and acetic anhydride were reacted at elevated temperature and the product of the reaction was crystallized through controlled cooling in such manner that the largest possible amount of the end product recovered thereby would be in the desired crystalline form most readily adapted to tableting. The end product was then filtered out, washed and dried but it was frequently necessary to resort to recrystallization to obtain the desired crystalline form of end product and to free it from impurities. The filtrate which was produced in this process was distilled to obtain additional quantities of the end product and also to recover solvents and unrelated reagents for recycling.

I have discovered that it is possible to prepare aspirin through a vastly simplified method which results in a very substantial reduction in-the cost'thereof, and it is a particular feature of my invention that the aspirin that can be produced thereby is not only substantially pure but it is also in the form of the desired needle-like crystals which most readily lend themselves to easy ta-bleting.

My method is based on the discovery that crystalline aspirin can be produced by heating a mixture of salicylic acid and a fractional molar excess of acetic anhydride and directly distilling to dryness at elevated temperatures and under reduced pressure; the acetic anhydride and salicylic acid can be reacted and distilled to dryness in a single step in one vessel from which nearly theoretical yields of substantially pure crystalline aspirin are directly obtained. This eliminates filtration, washing and drying of crystals and workup or refinement of process liquors, operations which require additional equipment and which are inherent in past methods.

A particularly surprising feature of my method is that distillation to dryness has produced aspirin of over 99.5% purity, whereas it would be anticipated on the basis of prior experience that impurities would be formed in excess of 0.5%. In addition to the high purity of my aspirin, near theoretical yields of aspirin and by-product acetic acid are obtained by my method. These high yields are primarily due to the fact that there is no occasion for loss of these materials through the precipitation, filtration, washing and reworking of mother liquors that have been necessary in the past.

The salicylic acid and acetic anhydride may be reacted and distillation of the reaction mixture under reduced pressure to recover liquids and to secure a crystalline product may be conveniently and satisfactorily carried out in apparatus such as stainless steel or glasslined blenders, ball mills and the like which are equipped to agitate the reaction mixture. I now prefer to use a conical, jacketed, dryer-blender of the type presently avail- 3,235,583 Patented Feb. 15, 1966 able on the market, but other like apparatus adapted to provide agitation, heat and means for liquid recovery may be employed.

In the practice of my invention, the method which I currently prefer consists in mixing acetic anhydride and salicylic acid in a glasslined jacketed, conical dryerblender which is revolvable on its central axis. I have found that an excellent yield of aspirin of exceptional quality can be obtained through the practice of my process when a slight molar excess of acetic anhydride is used. The quantity of acetic anhydride exceeds by about 2% to about 20% (18% being preferred) the stoichiometric equivalent of salicylic acid that is charged into the reaction vessel. An inert, organic diluent such as acetic acid, benzene, toluene or xylene may be added advantageously, but is not essential to the reaction. The reaction mixture is heated through the jacket of the dryerblender by the introduction of steam, or hot water or other suitable heat transfer medium to about 45 to C. Thereafter the pressure within the reaction vessel is reduced by exhaustion to produce a partial vacuum While maintaining a jacket temperature of about 45 95 C. The internal pressure is reduced initially to about -170 mm. of mercury absolute and progressively decreased at a rate of about 5 to 50 mm. per hour until visible distillation of liquids ceases. For complete removal of vapors and drying of the aspirin crystals, the pressure is preferably reduced to somewhere between the minimum obtainable in the system and 30 mm. and held at this pressure for several hours. The crystalline product is readily removed from the reactor by dumping.

While any inert diluent dlStlllEUbl6 under the above conditions may be used advantageously in the above method, acetic acid is particularly desirable since this permits the recovery of both the diluent and by-product acetic acid in a single step, in a relatively pure form suitable for recycling as the diluent for subsequent react-ions.

The percentage of impurities (normally less than .5% by U.S.P. test procedures) contained in the aspirin produced through my new method can be further reduced by introducing into the reaction vessel from 1 to 2% by weight based on the total weight of the reaction mixture, of a quench consisting of water or acetic acid or a mixture thereof.

The quench is introduced after substantially complete distillation of the reaction mixture and prior to dumping of the crystals, preferably shortly after minimum pressure is attained in the reaction vessel. The quench is added to prevent trace amounts of acetic anhydride (which might remain after distillation) from reacting with the aspirin crystals to form sodium carbonate insoluble compounds. While these sodium carbonate insoluble compounds, formed in the absence of a quench, appear to be unstable and disappear upon storage, they nevertheless prevent the crystals obtained directly from the reactor from passing the full U.S.P. test procedure. Thus, addition of the quench in large scale operations facilitates the recovery of U.S.P. aspirin crystals directly from the reaction vessel.

In order that my invention may be readily available to and understood by those skilled in the art, the following specific examples thereof are given:

Example I The following runs were made in a round bottomed Pyrex flask of 1,000 cubic centimeter capacity and the flask was attached to a rotary vacuum connection that would allow the flask to be laid upon its side and rotated in a water bath at elevated temperatures and reduced pressures.

(a) 140 grams of salicylic acid and 110 grams of acetic anhydride (a 6.8% molar excess) were heated at 75 C. for 90 minutes and the vacuum then applied at about 150 mm. of mercury absolute pressure. The vacdistillation under vacuum and then the acetic acid and finally the acetic anhydride were introduced by applying a slight vacuum to the unit. After loading, the blender was closed and started revolving, while water was circuuum was gradually lowered to about 30 of mercury 5 lated through the jacket at a temperature of 90 C. When absolute pressure over a period of about 90 minutes and the temperature within the unit reached about 88 C. as held at 30 mm. for an additional 30 minutes at said eleindicated by a dial thermometer installed in one of the vated temperature. A yield of 179 grams out of a theoloading ports, vacuum was applied and the pressure reretical of 181 grams of substantially pure aspirin crystals duced to about 170 mm. of mercury absolute pressure. was recovered directly from the flask. The U.S.P. test This pressure was held for one hour after which the abfor sodium carbonate insoluble materials on the product solute pressure was lowered approximately mm. of was negative indicating that no anhydride derivatives of mercury per hour for 4 /2 hours, at which point the abaspirin had been formed. Impurities oi about 1% unsolute pressure was lowered at a rate of 120 mm. of reacted salicylic acid, however, were found. mercury per hour for the next hour to the minimum ab- (b) 140 grams of salicylic acid, 120 grams of acetic 15 solute pressure attainable in the system; i.e., and 30 anhydride and 142 grams of toluene as a diluent were mm. of mercury absolute. During the controlled dcplaced in the flask and heated to 85 C. for about 40 crease in absolute pressure, the liquids in the reactor disminutes. The absolute pressure in the flask was reduced tilled at a steady rate and by the time that minimum abto 170 mm. pressure at said temperature and held for 3 solute pressure had been obtained the reactor contained hours. The absolute pressure was then gradually lowered 20 crystals of aspirin which were relatively dry. In this parto 2 mm, of mercury over a period of about 30 minutes, ticular series Of runs an additional 2 t0 3 hours at mini- Aspirin crystals were recovered directly from the flask mum Pressure Were allowed with the jacket m m and washed with carbon tetrachloride and dried in an temperature at ami crysfals w dumpea electric oven at 50 C. for 2 hours. 180 grams of aspirin welghed' Tests of crystals :[hls Series were were Obtained and 211 grams of solvent (toluene and stricted to an assay for percent aspirin and for free salicess acetic anhydride) and by-product acetic acid were recyhc acid Specified thg Rim t covered. The yield of aspirin based on salicylic acid was complete same? of tests for aspmn was.calr.led 99% of theoretical and the recovery of Solvent was and the material was satisfactory. A fluctuation n yield from 82% of the theoretical to 104% of theoretical will 96.5%. Melting polnt of finished material was 135-138 I be noted. This fluctuation in yield is due to the fact that Free Sahcyhc acld test and the a certain amount of materal adhered to the walls of the tenal assayed loo-1% t y test reactor in each run. The reactor was not cleaned between 140 grams of sahcyhc and, 122 grams of acetic runs so that after the first run or two almost theoretical hydride 175% molar eX6655) and 95 grams of acetic yields were obtained. It was observed by opening the reacid were reacted for 16 hours in the apparatus described actor that the material left on the walls from run to run above in a water bath held at C. The absolute presactually dissolved and therefore was eventually recovered.

TABLE I U.S.P. tests Run Notes reactor Salicylic acid, Acetic Acetic acid, Water jacket Aspirin yield, No. clean lbs. anhydride, lbs. temp, 0. percent of lbs. theory Aspirin assay Free salicylic Insolubility Other tests percent acid test tests 1 69 5s 25 90 s2 s9 56 25 90 92 69 5s 25 90 91 69 5s 25 90 100 69 5e 25 90 104 69 56 25 90 100 1 Test for materials insoluble sodium carbonate.

sure was reduced to 120 mm. of mercury to produce Example III distillation and gradually reduced to 20 mm. of mercury Data presented in Table H represent runs d i a until a y lltmduct Was Obtainfid (about 2 hours)- Thls plant or commercial scale 110 cubic foot glassline rotaryproduct was found to contain 35% unreacted salicylic acid with the rest being aspirin. The recovered weight of dry material was 163 grams which checks closely with the theoretical weight that should be obtained for a mixture of 65% aspirin and 35% salicylic acid, resulting from the starting materials. U.S.P. test for materials insoluble in sodium carbonate solution was negative.

((1) The above run was repeated without the acetic acid. In this case the mixture was held at 45 C. for 20 hours before distillation was started, and the resulting dry crystals contained only 20% unreacted salicylic acid. The total solids recovered were 1g70 grams. The above two runs indicate that the reaction can be expected to proceed toward completion as the time is increased at these relatively low temperatures.

Example 11 The runs included in Table I were carried out as follows: Salicylic acid was loaded directly into a five cubic foot glasslined, jacketed, conical dryer-blender adapted for conical vacuum-dryer made by Glasscote Products, Inc., and similar in design to the S-cubic foot unit used to collect the data in Table I. A manufacturing change from the small scale work was the installation of a 400-gallon glassline jacketed scale or weighing tank into which the salicylic acid, the acetic acid, and the acetic anhydride were charged. Water was circulated through the jacket of this tank at 88 C. and the tank agitated until solution was obtained. By adding warm acetic acid and acetic anhydride to this tank, solution was obtained in approximately the same elapsed time as in the smaller unit. With the material in solution, vacuum was applied to the reactor (the dryer blender) and the solution in the scale tank was pulled through a stainless steel filter into the reactor. The use of the scale tank allows convenient, accurate weighing of all ingredients and also permits filtration of the reaction mixture, a desirable precaution even when using U.S.P. quality raw materials. After the solution was in the reactor, the cycle was quite similar to the smaller runs. The pressure was reduced and held for one hour of acetic acid was approximately 75% due to the many opportunities for losses inherent in the processes.

Water jacket temp, C. U.S.P. tests Acetic an- Aspirin, Acetic Run Notes re- Salicylic hydride, Acetic yield peracid, yield N0 actor clean acid, lbs. lbs. acid, lbs. cent of percent of Above Below theory theory Aspirin Free sali- Insolubfl Other break break assay, percylic acld tests point point cent test my tests 2 7 Yes 1,395 1,119 626 88 98.5 97 99.83 OK 8 Yes 1, 395 1,119 626 88 50 99.2 95 99.99 OK 9 Yes 1, 395 1,122 626 88 72 98.9 97.5 99.99 OK 10 Yes 1, 395 1,122 626 88 72 99.0 96.0 99.523 OK 1 Steam 0d. 2 Test for materials insoluble sodium carbonate.

hours and at this point the pressure was reduced at the rate What I claim is: of 120 mm. per hour until a minimum absolute pressure 1. In the method of preparing acetyl salicylic acid by of 20 to 30 mm. of mercury was attained. At the break reacting a mixture of salicylic acid and acetic anhydride point where the more rapid decrease in absolute pressure at an elevated temperature of 40 C. to 95 C. the imwas begun, various temperatures of the water circulating provement which comprises: in the reactor jacket were tried as indicated m the table. employing a molar excess of about 2 to about 20% of In the large scale runs the addition of water or Water acetic anhydride; mixed with acetic acid, provided a practical method of reacting said mixture in a closed vacuum equipped vespreventing the formation of materials isoluble in sodium sel at said elevated temperature; carbonate. In Run No. 7, 10 lbs. of water in lbs. of maintaining said elevated temperature and reducing the acetic acid were added when the absolute pressure reached internal pressure to a partial vacuum within the range its minimum point; i.e., 20-30 mm. In Run No. 8, 20 lbs. 30 of about 120 mm. to 170 mm. of mercury absolute of water in 20 lbs of acetic acid where added at approxi and thereafter gradually reducing said pressure to a mately the same point. In Run No. 9, 20 lbs. of water in range between about 30 mm. and the minimum pres- 20 lbs. of acetic acid were added at the point at which visisure obtainable in the system; ble distillation had ceased, approximately 40 minutes afmaintaining said elevated temperature and reduced prester the minimum absolute pressure was reached. In Run sure at the lower range for about 1 to 3 hours; and No. 10, 20 lbs. of water in 20 lbs. of acetic acid were thereafter recovering acetyl salicylic acid directly from added at about 20 minutes after minimum pressure was said vessel in a pure dry crystalline form. reached. In each case the conditions were maintained 2. The method according to claim 1, wherein an inert until all distillation ceased. The material produced was distillable diluent selected from the group consisting of suitable for use preferably after deodorization and screenacetic acid, benzene, toluene and xylene is added to the reing. Removal of residual trace odors can be accomaction mixture prior to distillation. plished in various ways; (1) by application of an absolute 3. The method according to claim 1, wherein about 1% pressure in the range of 3 mm. of mercury for a period of to 2% by weight, based on the total weight of the reac about 40 minutes; (2) by drawing dry air at room temtion mixture, of a quench selected from the group conperature through the material for a period of 15 hours; or sisting of water, acetic acid and mixtures thereof, is added (3) by passing the material once through a standard tubu to said vessel after distilling to substantial dryness and lar hot air rotary dryer. one-half to two hours prior to recovery of the crystals The large scale reactor tests showed less of a tendency from said vessel. for the material to adhere to the walls as can be seen by the fact that starting with a substantially clean reactor, a References Cited by the Examine! yield of 99% of the theoretical based on salicylic acid was UNITED STATES PATENTS obtained in most cases. This high yield coupled withthe 2,423,569 7/1947 Sokol 260 480 good recovery of by-product acetic acid; i.e., 1n the ne1gh- 2,731,492 1/1956 Kamlet 26O 48O borhood of 97%, represents a substantial saving over 3,061,632 10/1962 Swim et a1 260 480 earlier aspirin processes where the over-all yield of aspirin was in the range of 91% of theoretical and the recovery LORRAINE A. WEINBERGER, Primary Examiner. 

1. IN THE METHOD OF PREPARING ACETYL SALICYCLIC ACID BY REACTING A MIXTURE OF SALICYCLIC ACID AND ACETIC ANHYDRIDE AT AN ELEVATED TEMPERATURE OF 40*C. TO 95*C. THE IMPROVEMENT WHICH COMPRISES: EMPLOYING A MOLAR EXCESS OF ABOUT 2 TO ABOUT 20% OF ACETIC ANHYDRIDE; REACTING SAID MIXTURE INA CLOSED VACUUM EQUIPPED VESSEL AT SAID ELEVATED TEMPERATURE; MAINTAINING SAID ELEVATED TEMPERATURE AND REDUCING THE INTERNAL PRESSURE TO A PARTIAL VACUUM WITHIN THE RANGE OF ABOUT 120 MM. TO 170 MM. OF MERCURY ABSOLUTE AND THEREAFTER GRADUALLY REDUCING SAID PRESSURE TO A RANGE BETWEEN ABOUT 30 MM. AND THE MINIMUM PRESSURE OBTAINABLE IN THE SYSTEM; MAINTAINING SAID ELEVATED TEMPERATURE AND REDUCED PRESSURE AT THE LOWER RANGE FOR ABOUT 1 TO 3 HOURS; AND THEREAFTER RECOVERING ACETYL SALICYLIC ACID DIRECTLY FROM SAID VESSEL IN A PURE DRY CRYSTALLINE FORM. 